CAR-T cells for the treatment of blood and solid tumors

T cells with chimeric antigen receptors, more commonly known as CAR-T cells, are used in the immunotherapy of cancer. In CAR-T cell therapy, a patient’s own T cells are taken from their blood and engineered in a laboratory to express an antigen receptor that targets a specific molecule expressed by a patient’s cancer cells. CAR-T cells contain a target-specific extracellular domain fused to the internal domain of CD3-zeta, which may or may not be fused to one or more costimulatory domains. Finally, these cells are transfused back into the patient. These cancer-specific T cells are a powerful tool that track down and kill cancer cells.

The development of CAR-T cells began in the late 1980s-1990s and the technologies that ultimately led to their creation were first developed by immunologists Michel Sadelain and Zelig Eshhar.^1,2 At the time the first T cell engineering was taking place, most scientists did not believe that T cells would have much efficacy in the fight against cancer. Little could they have predicted that two decades later, CAR-T cells would be an FDA-approved treatment for adult and childhood cancer.

Indeed, the FDA has approved CAR-T cells for the treatment of acute lymphoblastic leukemia, or ALL, in both adults and children, and for the treatment of lymphoma.³ The CAR-T cells used to treat ALL target a molecule called CD19.⁴ CD19 is found normally on the surface of B cells, where it is involved in B cell development and activation. CD19 is expressed at normal or elevated levels on the malignant B cells of at least 80% of ALL patients, as well as at least 88% of B cell lymphomas and all B cell leukemias, making it a useful therapeutic target in blood cancer. CD19 CAR-T cells are in clinical trials for the treatment of lymphoma and leukemia.

Two types of CD19-targeting CAR-T cells have been developed.⁵ The first generation CD19 CAR-T cells had just a CD19 recognition domain. However, these cells had a low persistence in vivo and were not very effective as anti-cancer therapy. Second-generation CD19 CAR-T cells added the intracellular domain of a costimulatory molecule: either CD28 or 4-1BB, while third-generation CD19 CAR-T cells include the intracellular domains of both CD28 and 4-1BB, fused to the CD3-zeta intracellular domain. In a clinical trial, a direct comparison of a second- versus third-generation CD19 CAR-T cell for the treatment of lymphoma showed that the third-generation CAR-T cells proliferated and persisted in vivo better than the second-generation CAR-T cells.⁶ Other studies showed that third-generation CD19 CAR-T cells are also effective against leukemia.⁷

While CAR-T cell therapy has been extensively evaluated in hematologic malignancies, more recently, CAR-T cells have been developed for some solid tumors as well. For the treatment of neuroblastoma, a childhood cancer that is notoriously difficult to treat, CAR-T cells targeting either GD2 or CD171 have reached clinical trials⁸. In both cases, some patients had partial or complete responses. Clinical trials for this disease are ongoing. GD2-targeting CAR-T cells have also shown success for the treatment of glioma.⁹ and are in clinical trials for sarcoma. CAR-T cells targeting HER2, a receptor tyrosine-kinase that is overexpressed in many tumors, have also been explored as a treatment for sarcoma and glioma. In both cancers, some patients showed a clinical response to treatment, which included either stable disease or partial or complete tumor regression¹⁰

Multiple other targets of CAR-T cells are also being evaluated for solid tumors, and combination therapies are being explored as well. However, local immune suppression in the microenvironment of solid tumors makes CAR-T therapy more challenging for solid tumors compared to blood tumors. Current clinical trials are exploring the combination of CAR-T cells with checkpoint blockade immunotherapy, which activates the anti-tumor immune response. Early reports from a CAR-T plus anti-PD-1 checkpoint blockade in mesothelioma showed 72% response rate including both partial and complete responses.¹¹